EP0761672A1 - Cephalosporin containing in position 7 a substituted benzyloxyimino radical, processes for their preparation and intermediates for their preparation, their use as medicaments - Google Patents

Abstract

Syn isomer of cpds. of formula (I), and their salts, are new. In (I), R1-R3, R5 = H, halo, OH, 1-4C alkyl (opt. substd. by halo, 1-4C alkyloxy, SH etc.); R4 = OH or 1-8C acyloxy; R7 = H or (1-3C alkyloxy)carbonyl; A = e.g. H, an equivalent of alkali(ne earth) metal, Mg, ammonium or aminated organic base etc.; or CO2A = CO2-; wavy line shows that CH2R6 can be in E- or Z-position; R6 = e.g. quat. ammonium or gp. of formula (i); X = CH2, NH, O or S; and Y, T, U, V, W and Z = CH or N; with the provisos.

Description

The present invention relates to new cephalosporins comprising on the side chain in position 7, a substituted benzyloxyimino radical, their preparation process and intermediates, their application as medicaments, the compositions containing them and the new intermediates obtained.

isomère syn, sous forme de sels internes ou de sels avec les acides minéraux ou organiques ou avec les bases, formule dans laquelle :

• R₁, R₂, R₃ et R₅, identiques ou différents, représentent un atome d'hydrogène, un atome d'halogène ou un radical choisi dans le groupe constitué par les radicaux hydroxy, alkyle renfermant de 1 à 4 atomes de carbone éventuellement substitué par un ou plusieurs atomes d'halogène, alkyloxy renfermant de 1 à 4 atomes de carbone, mercapto, alkylthio renfermant de 1 à 4 atomes de carbone, nitro, cyano, amino, alkylamino renfermant de 1 à 4 atomes de carbone, dialkylamino renfermant de 2 à 8 atomes de carbone, carbamoyle, (alkylamino) carbonyle renfermant de 2 à 5 atomes de carbone, (dialkylamino) carbonyle renfermant de 3 à 9 atomes de carbone, carboxy, alcoxycarbonyle renfermant de 2 à 5 atomes de carbone, acyloxy renfermant de 1 à 8 atomes de carbone et
  
  dans lequel Rx et Ry identiques ou différents représentent un atome d'hydrogène ou un radical alkyle renfermant de 1 à 4 atomes de carbone,
• R₄ représente un radical hydroxy ou un radical acyloxy renfermant de 1 à 8 atomes de carbone,
• R₇ représente un atome d'hydrogène ou un radical alkyloxy-carbonyl, dans lequel le radical alkyloxy renferme de 1 à 3 atomes de carbone,
• A représente un atome d'hydrogène, un équivalent de métal alcalin, alcalino-terreux, de magnésium, d'ammonium ou d'une base organique aminée, ou A représente le reste d'un groupement ester facilement clivable, ou bien CO₂A représente CO₂ ^⊖ , le trait ondulé signifie que le groupement CH₂R₆ peut se trouver dans la position E ou Z et R₆ représente, sous forme d'ammonium quaternaire, un des radicaux suivants :
  
  dans lesquels m est égal à 1, 2 ou 3, X représente CH₂, NH, O ou S ;
• Q, J, Y, T, U, V, W et Z, identiques ou différents, représentent indépendamment les uns des autres CH ou N, étant entendu que chacun de ces radicaux cycliques contient de 1 à 5 hétéroatomes, qu'au moins un de ces hétéroatomes est l'atome d'azote et que ces radicaux cycliques peuvent être substitués par un ou plusieurs radicaux R ou R' ;
• R et R', identiques ou différents, représentent un atome d'hydrogène, un radical alkyle renfermant de 1 à 4 atomes de carbone, un radical alkyloxy renfermant de 1 à 4 atomes de carbone, un atome d'halogène, un radical cyano, un radical CO₂-Q₁, CO-NQ₁(Q₂), NQ₁(Q₂), SO₂-NQ₁(Q₂), CS-NH₂, NH-CO-Q₁, CH=N-OH, CH=N-O-Q₁, CH₂-CN, CH₂-S-Q₁, S-Q₁, dans lesquels Q₁ et Q₂, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle renfermant de 1 à 4 atomes de carbone, P₁, P₂ et P₃, identiques ou différents, représentent un radical alkyle renfermant de 1 à 4 atomes de carbone, éventuellement substitué par un des substituants indiqués ci-dessus pour R et R', le trait pointillé indique que P₁ et P₂ peuvent encore former avec l'atome d'azote auquel ils sont liés, un hétérocycle à 5 ou 6 chaînons.

The subject of the invention is the products of general formula (I):

syn isomer, in the form of internal salts or of salts with mineral or organic acids or with bases, formula in which:

• R ₁ , R ₂ , R ₃ and R ₅ , identical or different, represent a hydrogen atom, a halogen atom or a radical chosen from the group consisting of hydroxy and alkyl radicals containing from 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkyloxy containing from 1 to 4 carbon atoms, mercapto, alkylthio containing from 1 to 4 carbon atoms, nitro, cyano, amino, alkylamino containing from 1 to 4 carbon atoms, dialkylamino containing from 2 to 8 carbon atoms, carbamoyl, (alkylamino) carbonyl containing from 2 to 5 carbon atoms, (dialkylamino) carbonyl containing 3 to 9 carbon atoms, carboxy, alkoxycarbonyl containing 2 to 5 carbon atoms, acyloxy containing 1 to 8 carbon atoms and
  
  in which Rx and Ry, which are identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms,
• R ₄ represents a hydroxy radical or an acyloxy radical containing from 1 to 8 carbon atoms,
• R ₇ represents a hydrogen atom or an alkyloxy-carbonyl radical, in which the alkyloxy radical contains from 1 to 3 carbon atoms,
• A represents a hydrogen atom, an equivalent of an alkali, alkaline earth metal, magnesium, ammonium or an amino organic base, or A represents the remainder of an easily cleavable ester group, or alternatively CO ₂ A represents CO ₂ ^⊖ , the wavy line means that the CH ₂ R _{6 group} can be in the E or Z position and R ₆ represents, in the form of quaternary ammonium, one of the following radicals:
  
  in which m is 1, 2 or 3, X represents CH ₂ , NH, O or S;
• Q, J, Y, T, U, V, W and Z, identical or different, represent independently of each other CH or N, it being understood that each of these cyclic radicals contains from 1 to 5 heteroatoms, that at least one of these heteroatoms is the nitrogen atom and that these cyclic radicals can be substituted by one or more radicals R or R ';
• R and R ′, which may be identical or different, represent a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms, an alkyloxy radical containing from 1 to 4 carbon atoms, a halogen atom, a cyano radical, a radical CO ₂ -Q ₁ , CO-NQ ₁ (Q ₂ ), NQ ₁ (Q ₂ ), SO ₂ -NQ ₁ (Q ₂ ), CS-NH ₂ , NH-CO-Q ₁ , CH = N- OH, CH = NOQ ₁ , CH ₂ -CN, CH ₂ -SQ ₁ , SQ ₁ , in which Q ₁ and Q ₂ , identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 atoms carbon, P ₁ , P ₂ and P ₃ , identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms, optionally substituted by one of the substituents indicated above for R and R ', the dotted line indicates that P ₁ and P ₂ can also form, with the nitrogen atom to which they are linked, a 5 or 6-membered heterocycle.

By alkyl radical containing from 1 to 4 carbon atoms, is meant the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radical.

By alkyloxy radical containing from 1 to 3 and 1 to carbon atoms is meant the methoxy, ethoxy, propoxy, isopropoxy radical, as well as butoxy, isobutoxy, sec-butoxy or tert-butoxy.

By alkylthio radical containing from 1 to 4 carbon atoms, is meant the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secbutylthio or tert-butylthio radical.

By alkylamino radical containing from 1 to 4 carbon atoms is meant the methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, secbutylamino or tert-butylamino radical.

By dialkylamino radical containing 2 to 8 carbon atoms is meant in particular the dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ethyl methylamino, propyl methylamino, butyl methylamino or propyl ethylamino radical.

By (alkylamino) carbonyl radical containing from 2 to 5 carbon atoms is meant in particular the (methylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl, (isopropylamino) carbonyl or (butylamino) carbonyl radical.

By (dialkylamino) carbonyl radical containing 3 to 9 carbon atoms is meant in particular the (dimethylamino) carbonyl, (diethylamino) carbonyl or (dipropylamino) carbonyl radical.

The term “alkoxycarbonyl radical containing 2 to 5 carbon atoms” is understood to mean in particular the methoxycarbonyl or ethoxycarbonyl radical.

By acyloxy radical containing from 1 to 8 carbon atoms is meant in particular the acetoxy, propionyloxy or benzoyloxy radical.

By halogen atom is meant a fluorine, chlorine, bromine or iodine atom.

When P ₁ and P ₂ form a heterocycle with the nitrogen atom to which they are linked, it can in particular be a pyrrolidino, morpholino or piperidino ring.

When R ₄ represents an acyloxy radical, it is in particular the acetoxy, propionyloxy or benzoyloxy radical. Among the values of A, there may be mentioned an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of an equivalent of an organic base, for example methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris [(hydroxymethyl) amino] methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

The products of formula (I) can also be in the form of pure internal salt, in salified form or in form associated with the acids of the solution.

Among the acids with which the products of formula (I) can be salified, there may be mentioned, inter alia, acetic, trifluoroacetic, fumaric, maleic, tartaric, methanesulfonic, benzenesulfonic, paratoluenesulfonic, phosphoric, sulfuric, hydrochloric acids hydrobromic, hydroiodic.

Among the bases with which the products of formula (I) can be salified, mention may be made, among others, of the bases corresponding to the salts mentioned above. Examples of base salification are provided below.
In a preferred embodiment of the invention CO ₂ A represents CO ₂ ^⊖ .

The expression "in the form of quaternary ammonium" indicates that the radical R ₆ is linked by the or one of the nitrogen atoms which it contains.

A particular subject of the invention is the products of general formula (I) as defined above, in which R ₆ represents one of the following radicals:

A more particular subject of the invention is the products of general formula (I) as defined above in which R ₆ represents the quinoline, isoquinoline, 4- (methylthio) pyridinium, thièno [2,3-b] pyridinium radical, 1-methyl pyrrolidinium, N-methyl N-ethyl N- (2-amino 2-oxoethyl) aminium, imidazo (1,2-a) pyridinium or the radical 6,7-dihydro-5H-1-pyrindinium, those in which R ₃ and R ₄ each represent a hydroxy radical, those in which R ₂ and R ₅ each represent a chlorine or fluorine atom, those in which R ₂ represents a fluorine atom and those in which R ₂ represents a methoxy radical and one of R ₁ or R ₅ represents a chlorine atom.

• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R-(3-(E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) imidazo(1,2-a) pyridinium,
• le sel interne de (6R-(3-(E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) (((2,5-dichloro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) imidazo(1,2-a) pyridinium,
• le sel interne de (6R-(3-(E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) 6,7-dihydro 5H-1-pyrindinium,
• le sel interne de (6R- (3 (E), 6alpha, 7béta(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) 6,7-dihydro 5H-1-pyrindinium,
• le sel interne de (6R- (3 (E), 6alpha, 7béta(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) ((5-fluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R-(3(E), 6alpha, 7béta(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) ((méthoxycarbonyl) (3,4-dihydroxy 5-fluorophényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium.

The invention particularly relates to the products whose names follow:

• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((2,5-difluoro 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((2,5-dichloro 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((2,5-difluoro 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2- a) pyridinium,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-dichloro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2 -a) pyridinium,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-difluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H-1-pyrindinium,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en- 3-yl) 2-propenyl) 6,7-dihydro 5H-1-pyrindinium,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((methoxycarbonyl) (3,4-dihydroxy 5 -fluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline.

dans laquelle R₁, R₂, R₃, R₄ et R₅ sont tels que définis ci-dessus, est si nécessaire protégé en ses fonctions réactives et transformé ainsi en aldéhyde aromatique de formule (II_p) :

dans laquelle R_1p, R_2p, R_3p, R_4p et R_5p représentent respectivement les valeurs de R₁, R₂, R₃, R₄ et R₅ telles que définies précédemment ou une fonction réactive protégée, ledit aldéhyde de formule (II_p) est soit traité par un agent réducteur, pour obtenir l'alcool de formule (III) :

soit homologué en alpha-hydroxy acide de formule (III₁) :

acide que l'on estérifie en alpha-hydroxy ester de formule (III₂) :

dans laquelle Alc représente un radical alkyle renfermant de 1 à 4 atomes de carbone,
ester ou alcool de formule (III₂) ou (III) que l'on traite par le N-hydroxy phtalimide, le cas échéant en présence d'un agent activant, pour obtenir le dérivé de formule (IV) :

que l'on hydrolyse en hydroxylamine O-substituée de formule (V) :

que l'on condense avec un dérivé de l'acide 2-(2-amino thiazol-4-yl) 2-oxo acétique de formule (VI) :

dans laquelle R₈ représente un atome d'hydrogène ou un groupe protecteur de la fonction amine, pour former le dérivé de l'acide alpha-alkoxyimino acétique "syn" de formule (VII) :

dont on prépare le cas échéant, un dérivé fonctionnel, produit de formule (VII) ou dérivé fontionnel que l'on amidifie avec un ester du chlorhydrate de l'acide 7-amino 3-(3-halo 1-propényl) 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-2-carboxylique de formule (VIII) :

dans laquelle R₉ représente le reste d'un ester aisément clivable, pour conduire au dérivé de l'acide 7-(N-substitué amido) 3-(3-halo 1-propényl) 8-oxo 5-thia 1-azabicyclo-[4,2,0]oct-2-èn-2-carboxylique de formule (IX) :

que l'on transforme, le cas échéant, en analogue 3-(3-iodo propényle) de formule (X) :

que l'on traite avec une base de formule R₆ pour obtenir le produit de formule (XI) :

produit de formule (XI) à partir duquel le cas échéant, l'on isole les isomères (E) ou (Z) ou transforme les isomères (Z) en isomères (E), produit de formule (XI) que l'on soumet le cas échéant, à une ou plusieurs des réactions suivantes dans un ordre approprié :

• a) coupure par hydrolyse ou par action de la thiourée de tout ou partie des groupements protecteurs esters et des groupements de protection du radical amino ou des radicaux hydroxyles,
• b) estérification ou salification par une base du radical carboxylique,
• c) salification par un acide du radical amino,
• d) séparation des produits sous forme de mélange R,S en R et S.

The subject of the invention is also a process for preparing the products of formula (I) as defined above, characterized in that the aromatic aldehyde of formula (II):

in which R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above, is if necessary protected in its reactive functions and thus transformed into aromatic aldehyde of formula (II _p ):

in which R _1p , R _2p , R _3p , R _4p and R _5p respectively represent the values of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ as defined above or a protected reactive function, said aldehyde of formula (II _p ) is either treated with a reducing agent, to obtain the alcohol of formula (III):

either approved in alpha-hydroxy acid of formula (III ₁ ):

acid which is esterified into alpha-hydroxy ester of formula (III ₂ ):

in which Alc represents an alkyl radical containing from 1 to 4 carbon atoms,
ester or alcohol of formula (III ₂ ) or (III) which is treated with N-hydroxy phthalimide, if necessary in the presence of an activating agent, to obtain the derivative of formula (IV):

which is hydrolyzed to O-substituted hydroxylamine of formula (V):

which is condensed with a 2- (2-amino thiazol-4-yl) 2-oxo acetic acid derivative of formula (VI):

in which R ₈ represents a hydrogen atom or a group protecting the amine function, to form the derivative of alpha-alkoxyimino acetic acid "syn" of formula (VII):

a functional derivative, product of formula (VII) or functional derivative which is amidified with an ester of 7-amino 3- (3-halo 1-propenyl) 8-oxo hydrochloride, which is optionally prepared, 5-thia 1-azabicyclo [4,2,0] oct-2-en-2-carboxylic of formula (VIII):

in which R ₉ represents the remainder of an easily cleavable ester, to lead to the acid derivative 7- (N-substituted amido) 3- (3-halo 1-propenyl) 8-oxo 5-thia 1-azabicyclo- [4,2,0] oct-2-en-2-carboxylic of formula (IX):

which is converted, where appropriate, into a 3- (3-iodo propenyl) analog of formula (X):

which are treated with a base of formula R ₆ to obtain the product of formula (XI):

product of formula (XI) from which if necessary, the isomers (E) or (Z) are isolated or transforms the isomers (Z) into isomers (E), product of formula (XI) which is subjected if applicable, one or more of the following reactions in an appropriate order:

• a) cleavage by hydrolysis or by the action of thiourea of all or part of the ester protecting groups and of the amino radical or hydroxyl radical protecting groups,
• b) esterification or salification with a base of the carboxylic radical,
• c) salification with an acid of the amino radical,
• d) separation of the products in the form of a mixture R, S into R and S.

pour conduire au produit de formule (XI) telle que définie précédemment.The subject of the invention is also a variant of the process described above, characterized in that the O-substituted hydroxylamine of formula (V) is condensed to the product of formula (XII):

to lead to the product of formula (XI) as defined above.

The protected hydroxy functions that R _1p , R _2p , R _3p , R _4p and R _5p can represent are chosen from acyloxy groups such as, for example, formyloxy, acetoxy, propionyloxy, chloroacetoxy, bromoacetoxy, dichloroacetoxy, trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy, benzoylformoxy, p-nitro benzoyloxy. May also be mentioned the groups ethoxycarbonyloxy, methoxycarbonyloxy, propoxycarbonyloxy, 2,2,2-trichloro ethoxycarbonyloxy, allyloxycarbonyloxy, triméthylsilyléthoxycarbonyloxy, benzyloxycarbonyloxy, tert-butoxycarbonyloxy, 1-cyclopropyl ethoxycarbonyloxy, phtaloyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy and pivaloyloxy, phenylacetoxy, phenylpropionyloxy, mesyloxy, chlorobenzoyloxy, para-nitrobenzoyloxy, para-tert-butyl benzoyloxy, caprylyloxy, acryloyloxy, methylcarbamoyloxy, phenylcarbamoyloxy, naphtylcarbamoyloxy.

They can also be chosen from the phenoxy, 4-chloro phenoxy, tolyloxy or tert-butyl phenoxy, tolylsulfonyloxy, tetrahydropyrannyloxy, tetrahydrothiopyrannyloxy, methoxytetrahydropyrannyloxy, trityloxy, benzyloxy, 4-methoxy benzyloxy, benzhydryloxyethyloxyethoxyoxy radicals. alkoxy alkoxy-methoxy radicals such as methoxy ethoxy methoxy or also the trimethylsilylethoxymethoxy or trimethylsilylethoxy radicals.

Two adjacent hydroxy radicals can also be protected by forming a methylenedioxy, isopropylenedioxy, 1,1-cyclohexyl bis (oxy), diphenylmethylenedioxy, carbonate or hydroxy borannylbis (oxy) radical.

The protected hydroxy functions which R _1p , R _2p , R _3p , R _4p and R _5p can represent are preferably chosen from methoxyethoxymethoxy, propionyloxymethoxy, acetoxymethoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy, butyryloxymethoxy, valeryloxymethoxy groups. , pivaloyloxymethoxy, 2-acetoxy ethoxy, 2-propionyloxy ethoxy, 2-butyryloxy ethoxy, 2-iodoethoxy, 2,2,2-trichloro ethoxy, vinyloxy, allyloxy, ethynyloxy, propynyloxy, benzyloxy, 4-methoxy benzyloxy, 4-nitro benzyl , phenylethoxy, trityloxy, diphenylmethyloxy or 3,4-dimethoxyphenoxy.

Particularly preferred is the 2-methoxy ethoxymethoxy (MEM-O) group.

The residue of easily cleavable ester group which R ₉ represents is chosen in particular from butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxymethyl, ethoxymethyl, isopropyloxymethyl, alpha-methoxy ethyl, alpha-ethoxy ethyl, methylthiomethyl, ethylthiomethyl, isopropyl groups. , pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadecanoyloxymethyl, propyloyloxyethyl, 1-isopropylethyl, propionyloxyethyl, propionyloxyethyl, propionyloxyethyl, 1 ethyl, 2-butyryloxy ethyl, 1- (tert-butylcarbonyloxy) ethyl, 1-acetoxy propyl, 1-hexadecanoyloxy ethyl, 1-propionyloxy propyl, 1-methoxycarbonyloxy ethyl, methoxycarbonyloxymethyl, 1-acetoxy butyl, 1-acetoxy hexyl, 1- acetoxy heptyl, phthalidyl, 5,6-dimethoxy phthalidyl, tert- butylcarbonylmethyl, vinyl, allyl, 2-chloro allyl, ethynyl, propynyl, methoxy-carbonylmethyl, benzyl, 4-methoxy benzyl, 4-nitro benzyl, phenethyl, trityl, diphenyl methyl, phenyl, 4-chloro phenyl, tolyl, tert-butyl phenyl, 3,4-dimethoxy phenyl, methoxyethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butoxycarbonylmethyl, 2,2-ethylenedioxy ethyl, cyanoethyl, 2,2-dimethoxy ethyl, 2-chloro ethoxymethyl, (2- hydroxy ethoxy) ethyl, 2,3-epoxy propyl, 3-dimethylamino 2-hydroxy propyl, 2-hydroxy ethyl, 2-methylaminoethoxy-methyl, (2-amino ethoxy) methyl, 3-methoxy 2,4-thiadiazol-5- yl, tetrahydropyrann-2-yl, 1-methoxy 1-methyl ethyl, 2-hydroxy 1-methyl ethyl, isopropyl, carbamoylmethyl, chloromethyl, 2-chloro ethyl, 2,2,2-trichloro ethyl, 2-iodo ethyl, acetyl , methyl, 2-methylthio ethyl, thiocyanatomethyl, 2-chloro 1-acetoxy ethyl, 2-bromo 1-acetoxy ethyl, 2-fluoro 1-acetoxy ethyl, 2-methoxy 1-acetoxy ethyl, 2-methyl 1-acetoxy propyl, 1-methyl 1-acetoxy ethyl, 1- (methoxyacetoxy) ethyl, 1-acetyl carbonyloxyethyl, 1-hydroxy acetoxyethyl, 1- (2-thienyl) carbonyloxyethyl, 1 - (2-furyl) carbonyloxyethyl, 1- (5-nitro 2-furyl) carbonyloxyethyl, 1- (2-pyrrolyl) carbonyloxyethyl, 1- (propionyloxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (methoxyethoxycarbonyloxy) ethyl, 1- (allyloxycarbonyloxy) ethyl, isopropoxycarbonyl methyl, 1 - [(2,3-epoxy propyl) oxycarbonyloxy] ethyl, 1 - [(2-furyl) methoxycarbonyloxy] ethyl, 1 - [(2- fluoro ethoxy) carbonyloxy] ethyl, 1- (methoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) 1-methyl ethyl, (methoxycarbonyloxy) chloromethyl, 1- (methoxycarbonyloxy) 2-chloro ethyl, 1- (methoxycarbonyloxy) 2-methoxy ethyl, 1 - (methoxycarbonyloxy) allyl or 5-methyl 2-oxo 1,3-dioxol-4-yl.

The diphenylmethyl radical is more particularly preferred.

The protective group of the amino radical which R ₈ can represent can be, for example, a carbamoyl, methyl carbamoyl, phenylcarbamoyl, naphthylcarbamoyl group, as well as the corresponding thiocarbamoyls, an alkyl radical of 1 to 6 substituted or unsubstituted carbon atoms such as, preferably , trichloroethyl, tert-butyl or tert-amyl, an aralkyl radical such as benzyl, 4-methoxy benzyl, phenethyl, trityl, 3,4-dimethoxy benzyl or benzhydryl, a substituted or unsubstituted aliphatic, aromatic or heterocyclic acyl radical, such as for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl, chlorofluoroyl -nitro benzoyl, para-tert-butyl benzoyl, phenoxyacetyl, caprylyl, decanoyl, acryloyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl, oxalyl, succinyl, pivaloyl, lower alkoxycarbonyl or cycloalkoxycarbonyl, methoxycarbonoxycarbonyl 1-cyclopropyl-ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, trichloroethoxy carbonyl, an aralkoxycarbonyl group, such as benzyloxycarbonyl.

The trityl group is preferred.

The above list is not exhaustive, it is obvious that other groups protecting amines, known to those skilled in the art, groups known in particular in peptide chemistry, can also be used.

The reducing agent which is made to act on the aldehyde of formula (IIp) is in particular a hydride such as sodium borohydride or aluminum-lithium hydride or also diisobutylaluminum hydride.

The esterification of the alpha hydroxy acid of formula (III ₁ ) can be carried out by means known to those skilled in the art, in particular by the action of diazomethane in solution in methylene chloride or tetrahydrofuran.

The activating agent in the presence of which the N-hydroxyphthalimide is made to act can be a phase transfer agent. Such agents are known to those skilled in the art.

The hydrolysis of the phthalimide of formula (IV) is carried out by the action of hydrazine, preferably in the form of a hydrate.

The functional derivative of the acid of formula (VII) may for example be a halide, a symmetrical or mixed anhydride, the amide, the azide or an activated ester.

As an example of mixed anhydride, there may be mentioned for example that formed with isobutyl chloroformate and that formed with pivaloyl chloride and mixed carboxylic-sulfonic anhydrides formed for example with para-toluene sulfonyl chloride.

As an example of an activated ester, mention may be made of the ester formed with 2,4-dinitrophenol and that formed with hydroxybenzothiazole.

As an example of a halide, mention may be made of chloride or bromide.

The anhydride can be formed in situ by the action of N, N'-disubstituted carbodiimide, for example N, N-dicyclohexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, other solvents such as tetrahydrofuran, chloroform or dimethylformamide can be used.

When an acid halide is used and in general when an acid molecule is released during the reaction, the reaction is preferably carried out in the presence of a base such as sodium carbonates and acid carbonates or potassium, sodium acetate, triethylamine, N, N-diisopropyl ethyl amine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is generally less than or equal to room temperature.

It is also possible to act directly on a product of formula (VII) with a product of formula (VIII) in the presence of a carbodiimide such as diisopropylcarbodiimide or 1- (3-dimethylamino propyl) 3-ethyl carbodiimide (EDC). An example of such a preparation is given later in the experimental part.

The action of the reagents capable of introducing the radical R ₆ and leading to the product of formula (XI) is carried out under the following conditions:

When Hal represents, for example, a chlorine atom, a substitution of the chlorine atom with an iodine atom in the presence of sodium iodide can be carried out in situ or separately, and then the desired reagent is added, in the presence or not an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, acetone or methyl ethyl ketone.

It is also possible to act directly on the product of formula (IX) or (X), the reagent of formula R ₆ , in the presence of silver tetrafluoroborate.

The isomerism of the products of formula (XI) may be different from that of the products of formula (IX) or (X). In the case where the Z isomer is isolated, this isomer can be transformed into the E isomer according to the usual methods, in particular by the action of iodine.

Depending on the values of R ₈ , R ₉ , R _1p , R _2p , R _3p , R _4p and R _5p , the action on the product of formula (XI) of one or more hydrolysis agents, hydrogenolysis or the purpose of thiourea is to eliminate the radical R ₈ when the latter represents a protective group for the amino radical, to transform the radicals R _1p , R _2p , R _3p , R _4p and R _5p respectively into radicals R ₁ , R ₂ , R ₃ , R ₄ and R ₅ when these carry a group protecting the hydroxyl radicals and / or eliminating the radical R ₉ when the latter represents, among the easily cleavable ester groups, one of those that we want to eliminate.

However, it is of course possible to eliminate R ₈ and to transform the radicals R _1p , R _2p , R _3p , R _4p and R _5p respectively into radicals R ₁ , R ₂ , R ₃ , R ₄ and R ₅ when those these bear a protective group for hydroxyl radicals without touching the substituent R ₉ when the latter must be preserved. The nature of the reagents to be used in such a case is well known to those skilled in the art. One will find for example a description of the various methods of elimination of the various protective groups in the French patent BF 2,499,995. Examples of such reactions are given later in the experimental part.

Given the nature of the preferred protecting groups that are used: trityl for R ₈ , 2-methoxy ethoxy methyl to protect the hydroxy functions and 4-methoxy benzyl for R ₉ , the solvent-free trifluoroacetic acid / anisole mixture is preferably used or in a solvent such as methylene chloride. We then obtain a salt with trifluoroacetic acid. If desired, it is possible to return to the free base by the action of a base such as a carbonate or triethylamine.

The salification of the products can be carried out according to the usual methods; it can for example be obtained by action on a product in acid form or on a solvate, for example the ethanolic solvate, or a hydrate of this acid, of a mineral base such as sodium or potassium hydroxide, carbonate or sodium or potassium acid carbonate. It is also possible to use the salts of mineral acids such as trisodium phosphate. It is also possible to use salts of organic acids such as for example, the sodium salts of aliphatic carboxylic acids, linear or branched, saturated or unsaturated from 1 to 18 and preferably from 2 to 10 carbon atoms. The aliphatic chains of these acids can be interrupted by one or more heteroatoms such as oxygen or sulfur or substituted by aryl radicals such as phenyl, thienyl or furyl, by one or more hydroxyl radicals or by one or more atoms of halogen such as fluorine, chlorine or bromine, preferably chlorine, by one or more carboxylic or lower alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, by one or more aryloxy radicals, preferably phenoxy.

In addition, it is possible to use as organic acids, sufficiently soluble aromatic acids such as, for example, benzoic acids substituted, preferably by lower alkyl radicals.

As examples of such organic acids, mention may be made of formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic, chloropropionic, crotonic, phenyl acetic, (2-thienyl) acetic, (3-thienyl) acetic acids. , (4-ethyl phenyl) acetic, glutaric, monoethyl ester of adipic acid, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxy propionic, 3-methoxy propionic, 3-methyl thiobutyric acid, 4-chloro butyric, 4-phenyl butyric, 3-phenoxy butyric, 4-ethyl benzoic, 1-propyl benzoic.

However, preferably used as sodium salts, sodium acetate, sodium 2-ethyl hexanoate or sodium diethyl acetate.

Salification can also be obtained by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethyl ethanolamine, tris [(hydroxymethyl) amino] methane, methylamine, ethanolamine , pyridine, picoline, dicyclohexyl amine, morpholine and benzylamine.

It can also be obtained by the action of arginine, lysine, procaine, histidine, N-methyl glucamine.

This salification is preferably carried out in a solvent or a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone.

The salts are obtained in amorphous or crystallized form according to the reaction conditions employed.

The crystallized salts are preferably prepared by reacting the free acids with one of the salts of the aliphatic carboxylic acids mentioned above.

The salification of the products with mineral or organic acids is carried out under the usual conditions.

The possible esterification of the products is carried out under conventional conditions. In general, the reaction is carried out by reacting the acid of formula (I) or a functional derivative with a derivative of formula:

Z-Re

in which Z represents a hydroxyl radical or a halogen atom such as chlorine, bromine, iodine and Re denotes the ester group to be introduced, a group of which a non-exhaustive list is given above. In some cases, it may be advantageous to carry out an esterification on a product in which the amine and / or the reaction groups present on the oxyimino are blocked before removing the group protector of the amine and of the reaction group present on the oxyimino.

The products of formula (I) contain several asymmetric carbons. In the cephem nucleus, which has two asymmetric carbons, the two carbons are in the R configuration. In addition, the radical present on the oxyimino function can also comprise an asymmetric carbon which can be in R or S form or in the form of a R + S mixture. The separation of the two diastereoisomers can be carried out by means known to those skilled in the art, for example by chromatography.

The products of general formula (I) have very good antibiotic activity on gram ^⊕ bacteria such as staphylococci, streptococci and in particular on penicillin-resistant staphylococci. Their effectiveness on enterobacteria producing chromosomal or plasmid β-lactamases is particularly remarkable.

These properties make said products as well as their pharmaceutically acceptable acid salts suitable for use as medicaments in the treatment of infections with sensitive germs and in particular in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal disease of the face or pyoderma. , septic or suppurative wounds, carbuncles, phlegmons, erysipelas, acute primary or post influenza staphylococcias, bronchopneumonia, pulmonary suppurations, meningitis, as well as in the treatment of infections in immunosuppressed patients.

These products can also be used as drugs in the treatment of colibacillosis and associated infections, in proteus, klebsiella and salmonella infections and in other conditions caused by gram ^⊖ bacteria.

The present invention therefore also has as an object, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and A are as defined above and R ₇ represents a hydrogen atom or an alkyloxycarbonyl radical, in which the alkyloxy radical contains from 1 to 4 carbon atoms, with the exception of tert-butyloxy, as well as their pharmaceutically acceptable acid salts.

The compounds in which R ₇ is an alkyloxy of 4 carbon atoms, known as intermediates (cleavable esters) in particular in French and European applications FR.A. 2,694,995, EP.A. 0 551 034 and 0 462 009 had never been described as medicinal products except when R ₇ is a tert-butyloxy

The subject of the invention is particularly, as medicaments, the preferred products of formula (I) as described above and in particular in which R ₆ is chosen from the quinoline, isoquinoline, 4- (methylthio) pyridinium and thièno radicals [2 , 3-b] pyridinium, 1-methyl pyrrolidinium, N-methyl N-ethyl N- (2-amino 2-oxoethyl) aminium, imidazo (1,2-a) pyridinium and 6,7-dihydro 5H-1-pyrindinium .

• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) (((2,5-dichloro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) imidazo(1,2-a) pyridinium,
• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) (((2,5-fluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0] oct-2-èn-3-yl) 2-propényl) imidazo (1,2-a) pyridinium,
• le sel interne de (6R- (3- (E) 6alpha, 7béta-(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) (((2,5-fluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) 6,7-dihydro-5H-1-pyrindinium,
• le sel interne de (6R-(3(E), 6alpha, 7béta(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) (((2,5-dichloro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) 6,7-dihydro-5H-1-pyrindinium,
• le sel interne de (6R-(3(E), 6alpha, 7béta (Z))) 1- (3- (7-(((2-amino 4-thiazolyl) ((5-fluoro 3,4-dihydroxyphényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,
• le sel interne de (6R-(3(E), 6alpha, 7béta(Z))) 1- (3- (7-(((2-amino 4-thiazolyl) ((méthoxycarbonyl) (3,4-dihydroxy 5-fluorophényl) méthoxy) imino) acétyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-èn-3-yl) 2-propényl) quinoléinium,

ainsi que leurs sels pharmaceutiquement acceptables.The subject of the invention is more particularly, as medicaments and in particular antibiotic medicaments, the products whose names follow:

• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-difluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-dichloro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-difluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2 -a) pyridinium,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl)) (((2,5-fluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2 -a) pyridinium,
• the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) (((2,5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en -3-yl) 2-propenyl) 6,7-dihydro-5H-1-pyrindinium,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) (((2,5-dichloro 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) 6,7-dihydro- 5H-1-pyrindinium,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,
• the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino 4-thiazolyl) ((methoxycarbonyl) (3,4-dihydroxy 5 -fluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline,

as well as their pharmaceutically acceptable salts.

The invention extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments defined above.

These compositions can be administered by buccal, rectal, parenteral route, in particular intramuscularly or by local route in topical application on the skin and the mucous membranes.

The products of formula (I) and in particular those in which A represents a cleavable ester can be administered orally.

The compositions according to the invention can be solid or liquid and can be in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers , conservatives.

These compositions can in particular be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example, sterile pyrogen-free water.

The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 0.250 g and 4 g per day, orally in humans, with the product described in Example 1 or even between 0.500 g and 1 g three times a day intramuscularly .

The products of formula (I) can also be used as disinfectants for surgical instruments.

The subject of the invention is finally, as new industrial products and in particular as intermediate products necessary for the preparation of the products of formula (I), the products of formulas (IV), (V), (VII), ( IX), (X) and (XI) as defined above.

The products of formula (II) are generally known and for the most part marketed; others can be prepared from marketed products, according to the methods described in European application 0551034. For the preparation of products of formula (II), one can also use the methods described in the literature, in particular the so-called Rosemund reduction , reduction of benzoic acids, or the formylation of aromatic rings such as for example the Vilsmeier-Haack reaction, the Gatterman-Koch reaction, the Reimer-Tiemann reaction or the reaction with formyl fluoride (J. Am. Chem Soc. 82, 2380 (1960)).

The products of formulas (VI) and (VIII) are also known in the literature, in particular in the Belgian patent applications BE864828 and European patent EP0333154.

The preparation of the products of formula (XII) is described in European application 0551034.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - (((2-amino-4-thiazolyl) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium. Stage A : Alcohol 2,5-dichloro 3,4-bis (2-methoxyethoxy) methoxy benzyl.

To a solution of 16.1 g of 2,5-dichloro-3,4-bis- (2-methoxyethoxy) methoxy benzaldehyde in 200 ml of methanol, 1.59 g of borohydride are added in portions at 0 ° C sodium. The mixture is stirred for 30 minutes at 0 ° C. and then 2.4 ml of acetic acid are added, allowing the temperature to return to ambient. Evaporated to dryness under reduced pressure and the residue is taken up in 80 ml of ethyl acetate, washed with a salt water solution, dried, filtered and evaporated to dryness under reduced pressure, 13.6 g of sought product is thus collected used as is for the next stage.
IR CHCl ₃ spectrum
OH: 3610 cm ^-1
Aromatic: 1555 cm ^-1
NMR spectrum CDCl ₃
3.38 (m): CH ₃ from OMEM; 3.58 (m) 4.00 (m) 5.24 (s) 5.25 (s): CH ₂ from OMEM; 4.78 (s): CH ₂ alcohol; 7.35 (s): Aromatic H.

Stage B : (2,5 dichloro-3,4-bis (2-methoxyethoxy) methoxy) -phenyl) ((1,3-dihydro 1,3 dioxo-2H-isoindol-2yl) oxy) methyl.

To a solution, cooled to 0 ° C of 18.39 g of triphenyl phosphine in 150 ml of tetrahydrofuran, 11.09 ml of diethyl azodicarboxylate is added dropwise, without exceeding + 5 ° C, the mixture is stirred for 15 minutes and added in portions 11.43 g of N-hydroxyphthalimide. The mixture is cooled to 0 ° C. and a solution of 13.6 g of the product obtained in stage A above in 40 ml of tetrahydrofuran is added dropwise, after stirring for 1 hour at 0 ° C., it is brought to dryness under reduced pressure . The residue is taken up in 100 ml of ethyl acetate, washed with water, dried, filtered and evaporated to dryness under reduced pressure. 50 g of product are obtained which is chromatographed on silica eluting with a methylene chloride-ethyl acetate mixture 80-20. 17.9 g of sought product is collected.
IR spectrum:
1790 cm ^-1
1750 cm ^-1 C = O
1736 cm ^-1
1610 cm ^-1 aromatic
1560 cm ^-1
NMR spectrum CDCl ₃
3.38 (s): CH ₃ from OMEM; 3.57-3.98-5.25-5.27: CH ₂ from OMEM: 7.52 (s) -7.75 to 7.84 (m): aromatics.

Stage C : 2,5-dichloro-3,4-bis (2-methoxyethoxy) methoxy oxyaminobenzyl.

3324 cm^-1 :

CH₂ - ONH₂

1583 cm^-1 :

aromatique

1558 cm^-1 :

NH₂

Spectre R.M.N. CDCl₃
3,38 (s) : CH₃ ; 3,58 (m)-4,00 (m)-5,25 (s) : les CH₂ de OMEM ; 4,74 (s) : CH₂-ONH₂ ; 5,55 (s,1) : NH₂ ; 7,28 : aromatique.To a solution, cooled to 0 ° C., of 17.7 g of product obtained in stage B above, in 120 ml of dichloromethane, 3.24 ml of hydrazine hydrate is added and then the mixture is stirred for one hour at 0 ° C. The insoluble material is filtered and concentrated to dryness under reduced pressure, the residue is taken up in 50 ml of ethyl ether, washed with water, dried and evaporated to dryness under reduced pressure. The product obtained is chromatographed on silica, eluting with a methylene chloride-ethyl acetate mixture 80-20. 9.6 g of product are collected which is taken up in 80 ml of ethyl ether, washed with water, dried and evaporated to dryness under reduced pressure. 9.15 g of expected product are obtained. IR CHCl ₃ spectrum:

3324 cm ^-1 :

CH ₂ - ONH ₂

1583 cm ^-1 :

aromatic

1558 cm ^-1 :

NH ₂

NMR spectrum CDCl ₃
3.38 (s): CH ₃ ; 3.58 (m) -4.00 (m) -5.25 (s): CH ₂ from OMEM; 4.74 (s): CH ₂ -ONH ₂ ; 5.55 (s, 1): NH ₂ ; 7.28: aromatic.

Stage D : (Z) α (2,5-dichloro-3,4 bis ((2-methoxy-ethoxy) methoxy) phenyl methoxy imino) (2 - ((triphenylmethyl) amino) 4-thiazoleacetic acid.

3404 cm^-1 :

=C-NH

1620 cm^-1 :

COO^- / C=N

1592 cm^-1 1577 cm^-1 :

hétérocycle

1529 cm^-1 1493 cm^-1 :

aromatique

Spectre R.M.N. CDCl₃
3,35 (s) : CH₃ de OMEM ; 3,55 (m)-3,95 (m)-5,17 (s) -5,20 (S) : les CH₂ de OMEM ; 5,13 (s,l) : CH₂-O-N ; 6,54 (s,l) : H thiazole ; 7,20 à 7,28 : aromatique.To a suspension of 8.34 g of the product obtained in stage C with 80 ml of methanol, 9.5 g of oxo [2 - [(triphenylmethyl) amino] -thiazol-4-yl] acetic acid (described in Belgian patent application n ° 864828). Stir one hour and then evaporate to dryness. The residue is taken up in methylene chloride, washed with 0.1 N hydrochloric acid, dried, filtered and then concentrated to dryness. 20 g of product are collected which is chromatographed on silica eluting with a methylene chloride-methanol mixture. Chromatography a second time under the same conditions to obtain 13.51 g of the desired product. IR CHCl ₃ spectrum

3404 cm ^-1 :

= C-NH

1620 cm ^-1 :

COO ^- / C = N

1592 cm ^-1 1577 cm ^-1 :

heterocycle

1529 cm ^-1 1493 cm ^-1 :

aromatic

NMR spectrum CDCl ₃
3.35 (s): CH ₃ from OMEM; 3.55 (m) -3.95 (m) -5.17 (s) -5.20 (S): CH ₂ from OMEM; 5.13 (s, 1): CH ₂ -ON; 6.54 (s, 1): H thiazole; 7.20 to 7.28: aromatic.

Stage E : [6R (3 (E), 6α, 6β (Z))] 3- (3-chloro 1-propenyl) 7 - (((2,5-dichloro-3,4 bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

To a solution of 8.1 g of the product obtained in stage D in 40 ml of methylene chloride, 4.37 g of 7β-amino hydrochloride 3- (3-chloro 1-propenyl) 8-oxo 5-thia are added 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxyphenyl) methyl (described in European patent application No. 0333154), cooled to -5 ° C and introduced 2.33 g of dimethylamino propyl-ethyl-carbodiimide, the mixture is stirred for 2 hours 30 minutes at 0 ° C. The solution is then washed with 2 times 10 ml of phosphate buffer solution at pH 7, then with salt water, dried, filtered and evaporated to dryness under reduced pressure to obtain 10.54 g of product which is chromatographed on silica eluting with a methylene chloride-ethyl ether mixture 90-10. We collects 6.52 g of sought product.
NMR spectrum CDCl ₃
3.27 (d, j = 18) -3.45 (d, j = 18): CH ₂ S; 3.36-3.37 (s): CH ₃ from OMEM; 3.57-3.98 (m) and 5.15 to 5.35: CH ₂ from OMEM and CH ₂ -ON; 3.81: methoxy benzyl; 5.01-5.05 (d): NC H -CH-S; 5.91-5.93 (dd): N-CH-C H -S; 3.72 and 3.92 (dd, j = 12 & 8): CH ₂ Cl; 5.73 (dt, j = 11 & 8) and 6.24 (d, j = 11): -C H = C H -CH ₂ Cl (delta Z); 6.02 (dt) and 7.04 (d, j = 15): -C H = C H -CH ₂ Cl (delta E); 7.30 (m): trityl; 6.88 to 7.30: aromatics; 5.15 to 5.37: OC H ₂ -Φ.

Stage F : [6R (3 (E), 6α, 7β (Z))] 3- (3-iodo 1-propenyl) 7 - (((2,5 dichloro-3,4 bis ((2-methoxyethoxy) methoxy ) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4- methoxyphenyl) methyl.

To a solution of 3.1 g of the product obtained in Stage E, above, in 12.5 ml of acetone, 1.59 g of sodium iodide and an iodine crystal are added. The mixture is stirred for 40 minutes at room temperature, evaporated to dryness under reduced pressure and taken up in 10 ml of methylene chloride, washed with an aqueous solution of 10% sodium thiosulphate then with salt water, dried, filtered and concentrated to dryness under reduced pressure. 3.79 g of sought product is obtained which is used as it is for the following stage.

Stage G : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7 - (((((2,5-dichloro-3,4-bis - ((2- methoxyethoxy) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - (((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1- azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium.

3404 cm^-1 :

=C-NH

1788 cm^-1 :

C=O

1721 cm^-1 1689 cm^-1 1628 cm^-1 :

C=C

1613 cm^-1 :

C=N

1595 cm^-1 1529 cm^-1 :

aromatique

1517 cm^-1 1493 cm^-1 :

amide II

Spectre R.M.N. CDCl₃
3,34 (s) : CH₃ de OMEM ; 3,55 (m)-3,96 (m) et 5,13 à 5,31 : les CH₂ de OMEM et CH₂-O-N= ; 6,86 (d,mobile) : CO-NH ; 6,70 (s) : H thiazole ; 7,27 (m) : trityl ; 4,97 (d,j=5) : N-CH-CH-S ; 5,88 (dd,d ap. éch.) : N-CH-CH-S ; 6,90 à 7,27 : 4 H aromatiques ; 3,78 (s) : OCH₃ du benzyle ; 5,13 à 5,31 : CH₂-Φ ; 3,47 (d)-3,64 (d) : S-CH ₂- ; 6,51 (dt,j=15,5 & 6) : CH propényl ; 6,06 et 6,21 (ddl,j=15 & 6) : CH₂ propényl ; 7,98 à 10,45 : 7H quinoléine.To a solution of the compound, obtained in Stage F, in 3 to 4 ml of methylene chloride, 1.57 ml of redistilled quinoline is added. The solvent is evaporated off under reduced pressure and then stirred for 1 hour at ordinary pressure. Ethyl ether is added, the mixture is stirred for 30 minutes, drained, washed with ether and dried under reduced pressure. 4 g of product are collected which is chromatographed on silica eluting with a methylene chloride-methanol mixture 95-05. 2.18 g of sought product is collected. IR spectrum

3404 cm ^-1 :

= C-NH

1788 cm ^-1 :

C = O

1721 cm ^-1 1689 cm ^-1 1628 cm ^-1 :

C = C

1613 cm ^-1 :

C = N

1595 cm ^-1 1529 cm ^-1 :

aromatic

1517 cm ^-1 1493 cm ^-1 :

amide ii

NMR spectrum CDCl ₃
3.34 (s): CH ₃ from OMEM; 3.55 (m) -3.96 (m) and 5.13 to 5.31: CH ₂ from OMEM and CH ₂ -ON =; 6.86 (d, mobile): CO-NH; 6.70 (s): H thiazole; 7.27 (m): trityl; 4.97 (d, j = 5): NC H -CH-S; 5.88 (dd, from ap. Sample): NC H -CH-S; 6.90 to 7.27: 4 aromatic H; 3.78 (s): OCH ₃ of benzyl; 5.13 to 5.31: CH ₂ -Φ; 3.47 (d) -3.64 (d): SC H ₂ -; 6.51 (dt, j = 15.5 & 6): CH propenyl; 6.06 and 6.21 (dof, j = 15 & 6): CH ₂ propenyl; 7.98-10.45: 7H quinoline.

Stage H : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium.

1778 cm^-1 :

C=O (béta lactame)

1666 cm^-1 1594 cm^-1 :

hétérocycle

1544 cm^-1 :

aromatique

1532 cm^-1 :

amide II / COO^-

Spectre R.M.N. Diméthylsulfoxyde
6,96 (s) : 1H aromatique, 5,08 (s) : -CH₂-O-N= ; 9,74 (d,mob.) : NH ; 6,76 (s) : H thiazole ; 5,17 (d,j=5) : N-CH-CH-S ; 5,80 (dd,d ap. éch.) : N-CH-CH-S ; 3,51-3,72 (d,j =17,5)) : S-CH ₂- ; 6,38 (dt,j=15,5 & 6) : CH propényl ; 7,00 : l'autre CH propényl ; 5,89 (m) : CH₂ propényl ; 8,25 à 9,59 : 7H quinoléine.A solution of 2.1 g of the product obtained in Stage G in 20 ml of a solution cooled to 0 ° C of 10% anisole trifluoroacetic acid is stirred for 10 minutes at 0 ° C., then the temperature is allowed to rise and stirred for 2 hours 30 minutes at room temperature. Filtered, washed with a few milliliters of trifluoroacetic acid, cooled to 0 ° C and added 70 ml of ethyl ether. Stirred 10 minutes at 0 ° C and then 90 minutes at room temperature. Filtered, washed with three times 10 ml of ethyl ether and the product obtained is again stirred for one hour with 30 ml of ethyl ether. Filtered as above and dried under reduced pressure, 1.076 g of sought product is collected.
Nujol IR spectrum
OH / NH absorption

1778 cm ^-1 :

C = O (beta lactam)

1666 cm ^-1 1594 cm ^-1 :

heterocycle

1544 cm ^-1 :

aromatic

1532 cm ^-1 :

amide II / COO ^-

NMR spectrum Dimethylsulfoxide
6.96 (s): 1H aromatic, 5.08 (s): -CH ₂ -ON =; 9.74 (d, mob.): NH; 6.76 (s): H thiazole; 5.17 (d, j = 5): NC H -CH-S; 5.80 (dd, from ap. Sample): N-CH-C H -S; 3.51-3.72 (d, j = 17.5)): SC H ₂ -; 6.38 (dt, j = 15.5 & 6): CH propenyl; 7.00: the other CH propenyl; 5.89 (m): CH ₂ propenyl; 8.25-9.59: 7H quinoline.

EXAMPLE 2 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - (((2-amino-4-thiazolyl) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2-a) pyridinium. Stage A : [6R (3 (E), 6α, 7β (Z))] 3- (3-chloro 1-propenyl) 7 - (((2,5 dichloro-3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2- ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

By operating as in Stage F of Example 1 starting from 3.2 g of the product obtained in Stage E of Example 1, 3.55 g of sought product is obtained, used as it is for the following stage.

Stage B : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7- (((((2,5-dichloro-3,4-bis ((2-methoxyethoxy ) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2- ((((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2 a) pyridinium

3404 cm^-1:

=C-NH

1787 cm^-1 :

C=O

1720 cm^-1 1689 cm^-1 1648 cm^-1 :

C=C

1613 cm^-1 :

C=N

1600 cm^-1 1587 cm^-1 1528 cm^-1 :

aromatique

1517 cm^-1 1493 cm^-1 :

amide II

Spectre R.M.N. CDCl₃
3,33-3,34 (s) : CH₃ de OMEM ; 3,56 (m)-3,95 (m) et 5,10 à 5,50 : les CH₂ de OMEM et CH₂-O-N= ; 6,86 (d,mobile) : CO-NH ; 6,70 (s) : H thiazole ; 7,25 à 7,33(m) : trityl ; 4,99 (d,j=5) : N-CH-CH-S ; 5,88 (dd,d ap. éch.) : N-CH-CH-S ; 6,89 à 7,33 : 5 H aromatiques ; 3,78 (s) : OCH₃ du benzyle ; 5,10 à 5,50 : CH₂-Φ ; 3,47 (d)-3,60 (d,j=18) : S-CH ₂- ; 6,27 (d,j=16 & 6,3) et 7,15 (d,j=16) : les CH propényl ; 5,10 à 5,50 : CH₂ propényl ; 7,44 à 9,21 : 7H imidazo pyridine.By operating as in stage G of example 1 starting from 3.55 g of the product obtained in stage A above and using 0.69 ml of imidazo (1.2 a) pyridine, 4 was obtained, 05 g of the crude product and after chromatography on silica (eluent methylene chloride-methanol 96-4) 2.05 g of sought product.
IR spectrum

3404 cm ^-1 :

= C-NH

1787 cm ^-1 :

C = O

1720 cm ^-1 1689 cm ^-1 1648 cm ^-1 :

C = C

1613 cm ^-1 :

C = N

1600 cm ^-1 1587 cm ^-1 1528 cm ^-1 :

aromatic

1517 cm ^-1 1493 cm ^-1 :

amide ii

NMR spectrum CDCl ₃
3.33-3.34 (s): CH ₃ from OMEM; 3.56 (m) -3.95 (m) and 5.10 to 5.50: CH ₂ from OMEM and CH ₂ -ON =; 6.86 (d, mobile): CO-NH; 6.70 (s): H thiazole; 7.25 to 7.33 (m): trityl; 4.99 (d, j = 5): NC H -CH-S; 5.88 (dd, from ap. Sample): N-CH-C H -S; 6.89 to 7.33: 5 aromatic H; 3.78 (s): OCH ₃ of benzyl; 5.10 to 5.50: CH ₂ -Φ; 3.47 (d) -3.60 (d, j = 18): SC H ₂ -; 6.27 (d, j = 16 & 6.3) and 7.15 (d, j = 16): CH propenyl; 5.10 to 5.50: CH ₂ propenyl; 7.44 to 9.21: 7H imidazo pyridine.

Stage C : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7- ((((2-amino-4-thiazolyl)) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2-a) pyridinium.

1774 cm^-1 :

C=O (béta lactame)

1674 cm^-1 1620 cm^-1 :

aromatique

1528 cm^-1 :

amide II / COO^-

Spectre R.M.N. Diméthylsulfoxyde
6,96 (s) : 1H aromatique, 5,08 (s) : -CH₂-O-N= ; 9,72 (d,mob.) : NH ; 6,77 (s) : H thiazole ; 5,17 (d,j=5) : N-CH-CH-S ; 5,79 (dd,d ap. éch.) : N-CH-CH-S ; 3,53-3,72 (d,j=17,5)) : S-CH ₂- ; 6,25 (dt,j=15,5 & 6)-6,88 (d,j=16) : les CH propényl ; 5,89 (m) : CH₂ propényl ; 7,57 à 8,96 : 6H imidazo pyridine.By operating as in Stage H of Example 1 from 1.45 g of the product obtained in Stage B above, and using 14 ml of a solution of trifluoroacetic acid at 10% anisole, one obtains 0.678 g of sought product.
Nujol IR spectrum
OH / NH absorption

1774 cm ^-1 :

C = O (beta lactam)

1674 cm ^-1 1620 cm ^-1 :

aromatic

1528 cm ^-1 :

amide II / COO ^-

NMR spectrum Dimethylsulfoxide
6.96 (s): 1H aromatic, 5.08 (s): -CH ₂ -ON =; 9.72 (d, mob.): NH; 6.77 (s): H thiazole; 5.17 (d, j = 5): N-CH-CH-S; 5.79 (dd, from ap. Sample): N-CH-CH-S; 3.53-3.72 (d, j = 17.5)): SC H ₂ -; 6.25 (dt, j = 15.5 & 6) -6.88 (d, j = 16): CH propenyl; 5.89 (m): CH ₂ propenyl; 7.57 to 8.96: 6H imidazo pyridine.

EXAMPLE 3 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6.7 dihydro 5H-1-pyrindinium. Stage A : [6R (3 (E), 6α, 7β (Z))] 3- (3-chloro 1-propenyl) 7 - (((2,5 dichloro-3,4-bis - ((2-methoxyethoxy ) (methoxy) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of ( 4-methoxyphenyl) methyl.

By operating as in Stage F of Example 1 from 3.2 g of the product obtained in Stage E of Example 1, 3.33 g of sought product is obtained, used as it is for the following stage.

Stage B : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7- (((((2,5-dichloro-3,4-bis - ((2- methoxyethoxy) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - (((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1- azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6,7 dihydro 5H-1-pyrindinium.

3404 cm^-1 :

=C-NH

1788 cm^-1 :

C=O

1720 cm^-1 1689 cm^-1 1614 cm^-1 :

C=N/C=C

1600 cm^-1 1587 cm^-1 1527 cm^-1 :

aromatique

1517 cm^-1 1492 cm^-1 :

amide II

Spectre R.M.N. CDCl₃
3,34-3,35 (s) : CH₃ de OMEM ; 3,56 (m)-3,96 (m) et 5,13 (d)-5,33 (s,l) : les CH₂ de OMEM et CH₂-O-N= ; 6,89 : CO-NH ; 6,70 (s) : H thiazole ; 7,28 (m) : trityl ; 4,99 : N-CH-CH-S ; 5,89 (dd,d ap. éch.) : N-CH-CH-S ; 6,89 à 7,28 : 5 H aromatiques ; 3,78 (s) : OCH₃ du benzyle ; 5,13 à 5,33 : CH₂-Φ ; 3,55-3,68 (d,j=18) : S-CH ₂- ; 6,37 (d,j=16 & 6,5) et 7,02 (d,j=16) : les CH propényl ; 5,49 à 5,60 : CH₂ propényl ; 2,41 à 9,14 : 9H pyrindinium.By operating as in Stage G of Example 1 starting from 3.33 g of the product obtained in Stage A above and using 1.60 ml of (2,3) cyclo penteno pyridine, 3.55 was obtained g of the crude product and after chromatography on silica (eluent methylene chloride-methanol (96-4)) 2.20 g of sought product.
IR spectrum

3404 cm ^-1 :

= C-NH

1788 cm ^-1 :

C = O

1720 cm ^-1 1689 cm ^-1 1614 cm ^-1 :

C = N / C = C

1600 cm ^-1 1587 cm ^-1 1527 cm ^-1 :

aromatic

1517 cm ^-1 1492 cm ^-1 :

amide ii

NMR spectrum CDCl ₃
3.34-3.35 (s): CH ₃ from OMEM; 3.56 (m) -3.96 (m) and 5.13 (d) -5.33 (s, l): CH ₂ from OMEM and CH ₂ -ON =; 6.89: CO-N H ; 6.70 (s): H thiazole; 7.28 (m): trityl; 4.99: NC H -CH-S; 5.89 (dd, from ap. Sample): N-CH-C H -S; 6.89 to 7.28: 5 aromatic H; 3.78 (s): OCH ₃ of benzyl; 5.13 to 5.33: CH ₂ -Φ; 3.55-3.68 (d, j = 18): SC H ₂ -; 6.37 (d, j = 16 & 6.5) and 7.02 (d, j = 16): CH propenyl; 5.49 to 5.60: CH ₂ propenyl; 2.41 to 9.14: 9H pyrindinium.

Stage C : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-dichloro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6.7 dihydro 5H-1-pyrindinium.

By operating as in Stage H of Example 1 from 2.18 g of the product obtained in Stage B above, and using 20 ml of a solution of trifluoroacetic acid at 10% anisole, one obtains 1.094 g of sought product.
Nujol IR spectrum
OH / NH absorption
1780 cm ^-1 : C = O (beta lactam)
1674 cm ^-1
NMR spectrum Dimethylsulfoxide
6.78 (s) -6.97 (s): 1H aromatic, 5.08 (s): -CH ₂ -ON =; 9.75 (d, mob.): NH; 6.78 (s) -6.97 (s): H thiazole; 5.19 (d, j = 5): NC H -CH-S; 5.82 (dd, from ap. Sample): N-CH-CH-S; 3.54-3.77 (d, d 18): SC H ₂ -; 6.25 (dt) -6.88 (d, j = 16): CH propenyl; 5.33 (d, 1): CH ₂ propenyl; 2.23 to 8.76: 9H pyrindinium.

EXAMPLE 4 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium. Stage A : Alcohol 2.5 difluoro 3,4-bis (2-methoxyethoxy) methoxy benzyl.

By operating as in Stage A of Example 1, starting from 21 g of 2.5 difluoro 3,4-bis (2-methoxyethoxy) methoxy benzaldehyde and using 2.26 g of sodium borohydride, 20 were obtained. , 53 g of sought product.
NMR spectrum CDCl ₃
3.36 (s): CH ₃ from OMEM; 3.56 (m) 3.94 (m) 5.22 (s) 5.24 (s): CH ₂ from OMEM; 4.67 (s): CH ₂ alcohol; 5.96 (s): aromatic H6.

Stage B : (2.5 difluoro-3,4 bis (2-methoxyethoxy) methoxy) -phenyl) ((1,3-dihydro 1,3-dioxo-2H-isoindol-2yl) oxy) methyl.

By operating as in stage B of Example 1, starting from 2 g of the alcohol obtained in stage A above and using 2.98 g of triphenyl phosphine, 1.79 ml of diethyl azodicarboxylate and 1, 38 g of N-hydroxyphthalimide. 890 mg of sought product was obtained.
NMR spectrum CDCl ₃
3.30 (s): CH ₃ from OMEM; 3.35-3.91-5.22-5.25: CH ₂ from OMEM; 5.20 (AB): NO-CH ₂ -Φ; 7.14 (dd): H6; 7.78: aromatics.

Stage C : 2.5 difluoro-3,4 bis (2-methoxyethoxy) methoxy oxyaminobenzyl.

By operating as in Stage C of Example 1, from 14.8 g of product obtained in Stage B above and 2.12 ml of hydrazine hydrate, after chromatography on silica is obtained (eluent: mixture methylene chloride-ethyl acetate 60-40) 7.2 g of the expected product.
IR CHCl ₃ spectrum:
3335 and 1585 cm ^-1 : CH ₂ -O-NH ₂
1630 and 1495 cm ^-1 _: aromatic
NMR spectrum CDCl ₃
3.37: O-CH ₃ ; 3.57 (m) -3.95 (m) -5.24 (s): CH ₂ from OMEM; 4.68 (m): CH ₂ -O-NH ₂ ; 5.49 (s, 1): N H ₂ ; 7.28: aromatic H6.

Stage D : (Z) α (2,5-difluoro-3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy imino) (2- ((triphenylmethyl) amino) 4-thiazoleacetic acid)

By operating as in stage D of Example 1, starting from 4 g of the product obtained in stage C above and using 4.92 g of oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid (described in Belgian patent application n ° 864828 ). After chromatography on silica (eluent: methylene chloride-methanol mixture 90-10), 7.53 g of sought product is obtained.
IR CHCl ₃ spectrum
3404 cm ^-1 : = C-NH
1607 cm ^-1 : COO ^- / heterocycle / aromatic:
1597 cm ^-1
1529 cm ^-1
1495 cm ^-1
NMR spectrum CDCl ₃
3.28 (s): O-CH ₃ from OMEM; 3.50 (m) -3.87 (m) -5.15 (s): CH ₂ from OMEM; 4.93 (s, 1): CH ₂ -ON; 6.45 (s, 1): H thiazole; 7.10 to 7.25: tityle; 6.88 (dd): aromatic H6.

Stage E : [6R (3 (E), 6α, 7β (Z))] 3- (3-chloro 1-propenyl) 7 - (((2,5 difluoro-3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

• pour ΔZ : 5,09 (d) : H6 ; 5,72 (dt) : -CH=CH-CH₂ ; 6,74 (d,j=8,5) : -CH=CH-CH₂
• pour ΔE : 4,99 : H6 ; 6,85 : -CH=CH-CH₂

By operating as in Stage E of Example 1, from 1.78 g of the product obtained in Stage D, and 780 mg of 7β-amino hydrochloride 3- [3-chloro 1-propenyl) 8-oxo 5- thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxyphenyl) methyl (described in European patent application No. 0333154), obtained after chromatography on silica (eluent: chloride chloride mixture methylene-ethyl acetate 80-20) 1 g of the desired product.
NMR spectrum CDCl ₃
3.30-3.44 (s): CH ₂ S; 3.33-3.35 (s): CH ₃ from OMEM; 3.55-3.92 (m) and 3.74 (dd): CH ₂ from OMEM, CH = CH-CH ₂ -X; 5.15-5.21 (AB) -5.31 (AB): O-CH ₂ -O from OMEM, CH ₂ -ON, OC H ₂ -Φ. ; 3.80: methoxy benzyl; 7.30 (m): trityl; 6.88: aromatics; 5.91 (dd): H7; 6.75: H5 thizole; 6.71 (d): CO-N H -CH; 6.98 (s): NH;

• for ΔZ : 5.09 (d): H6; 5.72 (dt): -C H = CH-CH ₂ ; 6.74 (d, j = 8.5): -CH = C H -CH ₂
• for ΔE : 4.99: H6; 6.85: -CH = C H -CH ₂

Stage F : [6R (3 (E), 6α, 7β (Z))] 3- (3-iodo 1-propenyl) 7 - (((2,5 difluoro-3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

By operating as in Stage F of Example 1 from 6 g of the product obtained as in Stage E above, and using 3.15 g of sodium iodide, 6.45 g of sought product was obtained which we use as is for the next stage.

Stage G : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7 - (((((2,5-difluoro-3,4-bis ((2-methoxyethoxy ) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2- ((((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinoline.

By operating as in stage G of example 1 starting from 2 g of the compound obtained in stage F, using 0.954 ml of quinoline, after chromatography on silica (688 mg of methylene chloride-methanol) is obtained product sought.

Stage H : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium.

By operating as in Stage H of Example 1 from 663 mg of the product obtained in Stage G, using 6 ml of trifluoroacetic acid at 10% anisole, 321 mg of sought product is collected.
NMR spectrum Dimethylsulfoxide
3.53-3.72 (d, j = 17.5): CH ₂ S; 5.04 (s): Φ-CH ₂ -O; 5.16 (d, j = 5): H6; 5.78 (dd, j = 5 & 8): H7; 5.88 (AB): = CH-C H 2-N ⁺ ; 6.38 (dt, j = 16 & 6): = C H -CH2-N ⁺ ; 6.69 (dd, j = 6 & 11): H6 '' (difluoro cycle); 6.75 (s): H thiazole 6.98 (d, j = 16): = CC H = CH-; 8.06 to 9.58: 7H 'quinoline; 9.69 (dj = 8, mobile): CO-N H -CH; 7.30-9.60: H mobile.

EXAMPLE 5 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) - methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2 -a) pyridinium. Stage A : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7- (((((2,5-difluoro-3,4-bis ((2-methoxyethoxy ) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - ((((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2 a) pyridinium

By operating as in stage G of example 1 starting from 2 g of the product obtained in stage F of example 4 and using 0.492 ml of imidazo (1.2 a) pyridine, one obtained after chromatography on silica (eluent methylene chloride-methanol (96-4)) 950 mg of the desired product.

Stage B : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -imidazo (1,2-a) pyridinium.

By operating as in Stage H of Example 1 from 940 mg of the product obtained in Stage A, above, and using 9 ml of a solution of trifluoroacetic acid at 10% anisole, 0.351 is obtained. g of product sought. NMR spectrum Dimethylsulfoxide
3.53-3.72 (d): CH ₂ S; 5.05 (s): Φ -CH ₂ -O; 5.17 (d): H6; 5.78 (dd): H7; 5.28 (m): = CH-C H 2-N ⁺ ; 6.25 (dt, j = 16 & 6): = C H -CH2-N ⁺ ; 6.70 (dd, j = 6 & 11): H6 '' (difluoro cycle); 6.76 (s): H thiazole; 6.98 (d, j = 16): = CC H = CH-; 7.57 to 8.44: 6H 'quinoline; 9.48 and 9.70 (d): CO-N H -CH; 7.30-9.65: H mobile.

EXAMPLE 6 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6,7-dihydro 5H-1-pyrindinium. Stage A : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7- (((((2,5-difluoro-3,4-bis ((2-methoxyethoxy ) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - (((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6,7-dihydro 5H-1-pyrindinium.

By operating as in Stage G of Example 1 starting from 2 g of the product obtained in Stage F of Example 4 and using 0.595 ml of (2,3) cyclo penteno pyridine, it was obtained after chromatography on silica ( eluent methylene chloride-methanol (96-4)), 899 mg of sought product.

Stage B : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7- ((((2-amino-4-thiazolyl)) (((2,5-difluoro-3 , 4-dihydroxyphenyl) -methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -6.7 dihydro 5H-1-pyrindinium.

By operating as in Stage H of Example 1 from 899 mg of the product obtained in Stage A above, and using 8 ml of a solution of trifluoroacetic acid at 10% anisole, 420 mg are obtained of product sought. NMR spectrum Dimethylsulfoxide
2.24 (m) -3.14 (t) -3.37 (t): pyrindinium; 3.55-3.78 (d): CH ₂ S; 5.06 (s): Φ-CH ₂ -O; 5.19 (d): H6; 5.81 (dd): H7; 5.34 (m): = CH-C H ₂ -N ⁺ ; 6.29 (dt) -6.87 (d, j = 16): CH = CH (Δ E); 6.72 (dd, j = 6.9 & 18): H6 '' (difluoro cycle); 6.78 (s): H thiazole; 7.92 (dd) -8.42 (d) -8.77 (d): H'5, H'4 and H'6; 9.74 (d): CO-N H -CH.

EXAMPLE 7 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7- ((((2-amino-4-thiazolyl)) (((3,4-dihydroxy-5 -fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinoline. Stage A : 5-Fluoro 3,4 bis (2-methoxyethoxy) methoxy benzyl alcohol.

The operation is carried out as in stage A of Example 1 starting from 9.2 g of 5-fluoro-3,4-dihydroxyphenyl) methoxy benzaldehyde using 1.02 g of sodium borohydride. 7.7 g of sought product is thus collected, used as it is for the following stage.

Stage B : (5-fluoro-3,4 bis (2-methoxyethoxy) methoxy) phenyl) ((1,3-dihydro 1,3-dioxo-2H-isoindol-2yl) oxy) methyl.

We operate as in stage B of Example 1 using 2.98 g of triphenyl phosphine and 1.79 ml of diethyl azodicarboxylate, 1.38 g of N hydroxyphthalimide, starting from 1.9 g of the product obtained in stage A above. 1.87 g of sought product are collected.
IR spectrum:
1794cm ^-1
1737 cm ^-1 C = O
1620 cm ^-1
1601 cm ^-1 aromatic
1510 cm ^-1
NMR spectrum CDCl ₃
3.36 (s) -3.38 (s): CH ₃ from OMEM; 3.56-3.89-3.96-5.12: OM ₂ CH ₂ : 7.01 to 7.75: aromatics.

Stage C : 5-fluoro 3,4-bis (2-methoxyethoxy) methoxy oxyaminobenzyl.

The procedure is carried out as in Stage C of Example 1 starting from 1.3 g of product obtained in Stage B above, using 0.2 ml of hydrazine hydrate. After chromatography on silica (eluting with a methylene chloride-ethyl acetate mixture 60-40), 710 mg of expected product is collected. IR CHCl ₃ spectrum:
3330cm ^-1 : CH ₂ -ONH ₂
1618, 1594, 1583 and 1509 cm ^-1 : aromatic + NH ₂ def. NMR spectrum CDCl ₃
3.37 (s) and 3.38 (s): CH ₃ ; 3.57 (m) -3.84 (m) -3.98 (m) -5.21 (s) -5.30 (s): CH ₂ from OMEM; 4.59 (s): CH ₂ - ONH ₂ ; 5.45 (s, 1): NH ₂ ; 6.81 (dd) -6.98 (m): aromatic.

Stage D : (Z) α (5-fluoro-3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy imino) (2 - ((triphenylmethyl) amino) 4-thiazoleacetic acid.

The procedure is carried out as in stage D of example 1 starting from 745 mg of the product obtained in stage C and using 650 mg of oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid (described in Belgian patent application No. 864828) to obtain 1.18 g of the desired product.
IR CHCl ₃ spectrum
3404 cm ^-1 : = C-NH
1593, 1577, 1530 and 1510: Conjugated system + aromatic NMR spectrum CDCl ₃
3.36 (s) -3.38 (s): CH ₃ from OMEM; 3.58 (m) - 3.80 (m) - 3.95 (m): CH ₂ from OMEM; 5.18 (s) -5.19 (s) -5.25 (s): CH ₂ -ON and O-CH2-O; 6.62 (s): H thiazole; 6.78 to 7.31: aromatic; 10.35 H mobile: CO2H.

Stage E : [6R (3 (E), 6α, 6β (Z))] 3- (3-chloro 1-propenyl) 7 - ((((5-fluoro 3,4-bis ((2-methoxyethoxy) methoxy)) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxyphenyl ) methyl.

The procedure is carried out as in Stage E of Example 1 starting from 1.1 g of the product obtained in Stage D and using 699 mg of 7β-amino hydrochloride 3- [3-chloro 1-propenyl) 8-oxo 5- thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxy phenyl) methyl (described in European patent application No. 0333154), and 336 mg of dimethylamino propyl ethyl carbodiimide, after chromatography on silica (eluent methylene chloride-ethyl ether 85-15), 860 mg of sought product is collected, used as it is for the following stage.

Stage F : [6R (3 (E), 6α, 7β (Z))] 3- (3-iodo 1-propenyl) 7 - (((5-fluoro 3,4-bis ((2-methoxyethoxy) methoxy)) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxyphenyl )methyl.

The procedure is carried out as in Stage F of Example 1 starting from 720 mg of the product obtained in Stage E, above, using 286 mg of sodium iodide and an iodine crystal. 770 mg of sought product is obtained which is used as it is for the next stage.

Stage G : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7 - ((((((5-fluoro 3,4-bis ((2-methoxyethoxy)) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - (((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo (4.2. 0) oct-2-en-3-yl) -2-propenyl) -quinoline.

770 mg of the product obtained in Stage F above is stirred for 1 hour at ambient temperature with 0.43 ml of redistilled quinoline. Precipitation is carried out by adding ethyl ether, draining, washing with ether and drying under reduced pressure. We collects 820 mg of product which is chromatographed on silica eluting with a methylene chloride-methanol mixture 96-04. 231 mg of sought product is collected. NMR spectrum CDCl ₃
3.78 - 3.93 (s): CH ₃ from OMEM; 3.42 (m) -3.54 (m) and 3.72 to 5.22: CH ₂ from OMEM and CH ₂ -ON =; 6.86 (d, mobile): CO-NH; 6.48 (s): H thiazole; 7.28: trityl; 4.98 (d): NC H -CH-S; 5.84 (d): N-CH-C H -S; 6.70 to 6.97: Aromatic H; 5.28: CH ₂ -Φ; 3.52 (d) -3.61 (d): SC H ₂ -; 6.42 (dt): CH propenyl; 6.03 (dd) and 6.17 (dd): CH ₂ propenyl; 8.14-10.4 (d): 7H quinoline.

Stage H : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((-3,4-dihydroxy- 5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinoline .

The operation is carried out as in Stage H of Example 1 from 120 mg of the product obtained in Stage G, using 1.2 ml of trifluoroacetic acid at 10% anisole, 31 mg of sought product is thus collected. NMR spectrum Dimethylsulfoxide
6.59 (m): Aromatic H, 4.92 (s): -CH ₂ -ON =; 9.66 (d, mob.): NH; 6.72 (s): H thiazole; 5.17 (d,): N-CH-CH-S; 5.78 (m): N-CH-CH-S; 3.52-3.74 (AB): SC H ₂ -; 6.98 (d, j = 15.5): CH propenyl; 6.38: the other CH propenyl; 5.90 (m): CH ₂ propenyl; 8.27 to 9.57: 7H quinoline.

EXAMPLE 8 Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - (((2-amino-4-thiazolyl) (((methoxycarbonyl) -3,4- dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium. Stage A : [3-fluoro 4,5-bis [(2-methoxyethoxy) methoxy] phenyl] hydroxy methyl acetate

5.3 g of [3-fluoro 4,5-bis [(2-methoxyethoxy) methoxy] phenyl] hydroxy-acetic acid (described in European patent application no. 551034) in 66 cm ³ of tetrahydrofuran then added at 15 ° C, 78 cm ³ of a solution of diazomethane in ether at 15 g / l (2 equivalents of diazomethane) and maintained under shaking for 16 h. Water is added and acidified by the addition of acetic acid. The organic phase is washed with a saturated sodium bicarbonate solution, dried and evaporated to dryness. 5.5 g of crude expected product are obtained, used as it is for the following stage.

Stage B : [3-fluoro 4,5-bis [(2-methoxy ethoxy) methoxy] phenyl] methyl phthalimidoxy acetate

2.25 g of N-hydroxy phthalimide and 7 g of triphenyl phosphine are added to a solution of 5.5 g of product obtained in stage A in 60 cm ³ of tetrahydrofuran. Cool to -10 ° C and add 4.1 cm ³ of diethyl azodicarboxylate and then stirred at 0 ° C for 2 hours. It is concentrated to dryness and the crude product is washed with isopropyl ether and then dried. 6.5 g of expected product are obtained.
IR spectrum (CHCl ₃ )
Absorption at 1745, 1759, 1739 cm ^-1 : C = O, 1615, 1597, 1509, 1490 cm ^-1 : C = C aromatic.

Stage C : methyl oxyamino [3-fluoro 4,5-bis [(2-methoxyethoxy) methoxy] phenyl] acetate

2 g of the product obtained in Stage B, 40 ml of ethanol, 4 ml of a 1 M solution of hydrazine hydrate in ethanol are stirred for 2 hours at 20 ° C. The insoluble material formed is filtered, rinsed with methylene chloride, added to the filtrate 20 ml of phosphate buffer, stirred for 5 minutes and extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. The residue is taken up in 5 ml of methylene chloride, stirred for 30 minutes at 0 ° C., filter rinsed with methylene chloride and the filtrate is concentrated to dryness under reduced pressure. 1.6 g of the sought product are collected. IR spectrum (Nujol)
OH / NH absorption
C = O 1751, 1722 cm-1
Aromatics 1615, 1590.1507 cm-1

Stage D : (Z) acid α - ((methoxycarbonyl) -5 fluoro 3,4-bis (((2-methoxyethoxy) methoxy) phenylmethoxy) carboxymethyl) imino) (2- ((triphenylmethyl) amino) 4-thiazoleacetic.

The procedure is carried out as in stage D of example 1 from 710 mg of the product obtained in stage C and using 747 mg oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid (described in Belgian patent application No. 864828) to obtain 1.14 g of sought product.
NMR spectrum CDCl ₃
3.36 (s) -3.42 (s): CH ₃ from OMEM; 3.56 (m) -3.64 (m) -3.82 (m) -3.965 (m): CH ₂ from OMEM; 3.79 (s): CO2 CH3 ; 5.21 (s) 5.20 to 5.28 (m): O-CH2-O; 5.80 (s): CH-ON; 6.78 (s): H thiazole; 6.88 to 7.32: aromatic.

Stage E : [6R (3 (E), 6α, 6β (Z))] 3- (3-chloro 1-propenyl) 7 - ((((methoxycarbonyl) 5-fluoro 3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

The procedure is carried out as in Stage E of Example 1 starting from 1.14 mg of the product obtained in Stage D and using 786 mg of 7β-amino hydrochloride 3- [3-chloro 1-propenyl) 8-oxo 5- thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4-methoxy phenyl) methyl (described in European patent application No. 0333154), and 378 mg of dimethylamino propyl ethyl carbodiimide, after chromatography on silica (eluent methylene chloride-ethyl ether 85-15), 1.01 g of sought product is collected, used as it is for the following stage.

Stage F : [6R (3 (E), 6α, 7β (Z))] 3- (3-iodo 1-propenyl) 7 - ((((methoxycarbonyl) 5-fluoro 3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2- ((triphenylmethyl) amino) 4- thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo (4.2.0) oct-2-ene-2-carboxylate of (4 -methoxyphenyl) methyl.

The procedure is carried out as in Stage F of Example 1 starting from 1 g of the product obtained in Stage E, above, using 380 mg of sodium iodide and an iodine crystal. 1.05 g of sought product is obtained which is used as it is for the following stage.

stage G : (6R (3 (E), 6α, 7β (Z))) iodide of 1- (3- (7 - (((((methoxycarbonyl) 5-fluoro 3,4-bis ((2-methoxyethoxy)) methoxy) phenyl) methoxy) imino) (2 - ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2 - ((((4-methoxyphenyl) methoxy) carbonyl) 8-oxo-5-thia-1-azabicyclo ( 4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium isomer (delta Z) and isomer (delta E).

The procedure is carried out as in Stage G of Example 7 starting from 1 g of the product obtained in Stage F above using 0.5 ml of redistilled quinoline. 0.99 g of expected product is collected.
CDCl ₃ NMR spectrum (delta Z isomer)
3.32-3.35-3.36 (s): CH ₃ from OMEM; 3.30 (m) to 4.05 (m) and 5.24 to 5.35: CH ₂ from OMEM; 5.86 (s) 5.87 (s) CH-ON =; 8.48 (d): NH; 6.76 to 7.35 (m): H thiazole and trityl; 5.42-5.47 (d): N-CH-CH-S; 5.97 (dd): N-CH-CH-S; 6.76 to 7.35: Aromatic H; 5.24 to 5.35: CH ₂ -Φ; 3.30 (m) -4.05 (m): SC H ₂ -; 6.51 (dl, j = 11): CH propenyl; 5.90 the other CH propenyl; 5.69 (dm, j = 16) -6.07 (ddl, j = 16 and 7.5): CH ₂ propenyl; 7.87 (m), 8.01 to 8.22 (m), 8.99 (dl), 10.30 (dl). Mixture R / S 80/20 with delta Z and syn oxime.
NMR spectrum CDCl ₃ (delta E isomer)
3.28-3.34-3.35 (s): CH ₃ from OMEM; 3.42 (m) to 4.00 (m) and 5.10 to 5.32: CH ₂ from OMEM; 5.81 (s) 5.84 (s) CH-ON =; 8.55 (d): NH; 6.78 to 6.80 (s): H thiazole; 6.85 to 7.40 trityl; 4.97-5.04 (d): NC H -CH-S; 5.88-5.94 (dd): NC H -CH-S; 6.85 to 7.40 (m): Aromatic H; 3.69-3.73-3.80-3.82: Φ-OCH3 and CO2CH3; 3.40 (m) -4.00 (m): SC H ₂ -; 6.38 to 6.63 (m): CH propenyl; 6.00-6.15 (m): CH ₂ propenyl; 7.94 (m), 8.15 (m), 8.26 (m), 8.43 (dl), 9.00 (d), 10.36 (m): quinoline. (Mixture R / S 35/65 with delta E and oxime syn.

Stage H : Internal salt of (6R (3 (E), 6α, 7β (Z))) 1-3- (7 - ((((2-amino-4-thiazolyl)) (((methoxycarbonyl) -3,4- dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-en-3-yl) -2-propenyl) -quinolinium.

The procedure is carried out as in Stage H of Example 1 from 300 mg of the product obtained in Stage G, using 3 ml of trifluoroacetic acid and 0.3 ml of anisole. 112 mg of the desired product are obtained.
IR spectrum (Nujol)
General absorption OH / NH
C = O 1770, 1742 and 1670 cm-1
Conjugated system, COO ^- and secondary amide 1627, 1590 and 1525 cm ^-1 .
NMR spectrum Dimethylsulfoxide
3.64-3.65 (s): CO2CH3; 6.69 (m) to 6.78 (m): Aromatic H and H thiazole; 5.46 (s): -CH-ON =; 5.12-5.16 (d): NC H -CH-S; 5.82 (m): NC H -CH-S; 3.52-3.70: SC H ₂ -; 6.96 (dded.): CH propenyl; 5.88 (m): CH ₂ propenyl; 8.07 to 9.58: 7H quinoline.

In addition to the products described above in the examples, the products corresponding to the formula below and resulting from combinations of the different values of the substituents represented in the tables which follow, constitute products which can be obtained according to the invention.

EXAMPLE 9 Preparations for injections with the formula:

• Product of Example 1,500 mg
• Sterile aqueous excipient qs 5 cm ³

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION In vitro activity, solid medium dilution method.

A series of boxes is prepared in which the same quantity of sterile nutritive medium is distributed, containing increasing quantities of the product to be studied, then each box is seeded with several bacterial strains.

After incubation for 24 hours in an oven at 37 ° C, the growth inhibition is assessed by the absence of any bacterial development which makes it possible to determine the minimum inhibitory concentrations (MIC) expressed in micrograms / cm ³ .

The results are expressed in the form of geometric means of all the MICs obtained, for a particular group of strains.

The following results were obtained (table):

Claims (14)

The products of general formula (I):

syn isomer, in the form of internal salts or of salts with mineral or organic acids or with bases, formula in which: R ₁ , R ₂ , R ₃ and R ₅ , identical or different, represent a hydrogen atom, a halogen atom or a radical chosen from the group consisting of hydroxy and alkyl radicals containing from 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkyloxy containing from 1 to 4 carbon atoms, mercapto, alkylthio containing from 1 to 4 carbon atoms, nitro, cyano, amino, alkylamino containing from 1 to 4 carbon atoms, dialkylamino containing from 2 to 8 carbon atoms, carbamoyl, (alkylamino) carbonyl containing from 2 to 5 carbon atoms, (dialkylamino) carbonyl containing from 3 to 9 carbon atoms, carboxy, alkoxycarbonyl containing from 2 to 5 carbon atoms, acyloxy containing 1 to 8 carbon atoms and

in which Rx and Ry, which are identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, R ₄ represents a hydroxy radical or an acyloxy radical containing from 1 to 8 carbon atoms, R ₇ represents a hydrogen atom or an alkyloxycarbonyl radical, in which the alkyloxy radical contains from 1 to 3 carbon atoms, A represents a hydrogen atom, an equivalent of an alkali, alkaline earth metal, magnesium, ammonium or an amino organic base, or A represents the remainder of an easily cleavable ester group, or alternatively CO ₂ A represents CO ₂ ^⊖ , the wavy line means that the CH ₂ R _{6 group} can be in the E or Z position and R ₆ represents, in the form of quaternary ammonium, one of the following radicals:

in which m is 1, 2 or 3, X represents CH ₂ , NH, O or S; Q, J, Y, T, U, V, W and Z, identical or different, represent independently of each other CH or N, it being understood that each of these cyclic radicals contains from 1 to 5 heteroatoms, that at least one of these heteroatoms is the nitrogen atom and these cyclic radicals can be substituted by one or more radicals R or R '; R and R ', identical or different, represent a hydrogen atom, an alkyl radical containing from 1 to 4 atoms of carbon, an alkyloxy radical containing from 1 to 4 carbon atoms, a halogen atom, a cyano radical, a CO ₂ -Q ₁ radical, CO-NQ ₁ (Q ₂ ), NQ ₁ (Q ₂ ), SO ₂ -NQ ₁ (Q ₂ ), CS-NH ₂ , NH-CO-Q ₁ , CH = N-OH, CH = NOQ ₁ , CH ₂ -CN, CH ₂ -SQ ₁ , SQ ₁ , in which Q ₁ and Q ₂ , identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, P ₁ , P ₂ and P ₃ , identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms carbon, optionally substituted by one of the substituents indicated above for R and R ', the dotted line indicates that P ₁ and P ₂ can still form, with the nitrogen atom to which they are linked, a 5 or 6-membered heterocycle . The products of general formula (I) as defined in claim, in which R ₆ represents one of the following radicals:

The products of general formula (I) as defined in claim 1 or 2, in which R ₆ represents the quinoline, isoquinoline, 4- (methylthio) pyridinium, thien [2,3-b] pyridinium, 1-methyl pyrrolidinium radical , N-methyl N-ethyl N- (2-amino 2-oxoethyl) aminium, imidazo (1,2-a) pyridinium or the radical 6,7-dihydro-5H-1-pyrindinium. The products of general formula (I) as defined in any one of claims 1, 2 or 3, in which R ₃ and R ₄ each represent a hydroxy radical. The products of general formula (I) as defined in any one of claims 1, 2, 3 or 4, in which R ₂ and R ₅ each represent a chlorine or fluorine atom. The products of general formula (I) as defined in any one of claims 1, 2, 3 or 4, in which R ₂ represents a fluorine atom. The products of general formula (I) as defined in any one of claims 1, 2, 3 or 4, in which R ₂ represents a methoxy radical and one of R ₁ or R ₅ represents a chlorine atom. The products of general formula (I) whose names follow: - the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((2,5-difluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline, - the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((2,5-dichloro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline, - the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((2,5-difluoro 3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2 -a) pyridinium, - the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) (((2,5-dichloro 3 , 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) imidazo (1,2-a) pyridinium, - the internal salt of (6R- (3- (E) 6alpha, 7béta- (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) (((2,5-difluoro 3 , 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) 6,7- dihydro 5H-1-pyrindinium, - the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((2,5-dichloro 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H -1-pyrindinium, - the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((5-fluoro 3,4-dihydroxyphenyl) ) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline, - the internal salt of (6R- (3 (E), 6alpha, 7beta (Z))) 1- (3- (7 - ((((2-amino 4-thiazolyl)) ((methoxycarbonyl) (3,4-dihydroxy 5-fluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl) 2-propenyl) quinoline. Process for preparing the products of formula (I) as defined in claim 1, characterized in that the aromatic aldehyde of formula (II):

in which R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1, is if necessary protected in its reactive functions and thus transformed into aromatic aldehyde of formula (II _p ):

in which R _1p , R _2p , R _3p , R _4p and R _5p respectively represent the values of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ as defined above or a protected reactive function, said aldehyde of formula ( II _p ) is either treated with a reducing agent, to obtain the alcohol of formula (III):

either approved in alpha-hydroxy acid of formula (III ₁ ):

acid which is esterified into alpha-hydroxy ester of formula (III ₂ ):

in which Alc represents an alkyl radical containing from 1 to 4 carbon atoms,
ester or alcohol of formula (III ₂ ) or (III) which is treated with N-hydroxy phthalimide, if necessary in the presence of an activating agent, to obtain the derivative of formula (IV):

which is hydrolyzed to O-substituted hydroxylamine of formula (V):

which is condensed with a 2- (2-amino thiazol-4-yl) 2-oxo acetic acid derivative of formula (VI):

in which R ₈ represents a hydrogen atom or a group protecting the amine function, to form the derivative of alpha-alkoxyimino acetic acid "syn" of formula (VII):

a functional derivative, product of formula (VII) or functional derivative which is amidified with an ester of 7-amino 3- (3-halo 1-propenyl) 8-oxo hydrochloride, which is optionally prepared, 5-thia 1-azabicyclo [4,2,0] oct-2-en-2-carboxylic of formula (VIII):

in which R ₉ represents the remainder of an easily cleavable ester, to lead to the acid derivative 7- (N-substituted amido) 3- (3-halo 1-propenyl) 8-oxo 5-thia 1-azabicyclo- [4,2,0] oct-2-en-2-carboxylic of formula (IX):

which is converted, where appropriate, into a 3- (3-iodo propenyl) analog of formula (X):

which are treated with a base of formula R ₆ to obtain the product of formula (XI):

product of formula (XI) from which if necessary, the isomers (E) or (Z) are isolated or transforms the isomers (Z) into isomers (E), product of formula (XI) which is subjected if applicable, one or more of the following reactions in an appropriate order: a) cleavage by hydrolysis or by the action of thiourea of all or part of the protecteuts ester groups and of the amino radical or hydroxyl radical protection groups, b) esterification or salification with a base of the carboxylic radical, c) salification with an acid of the amino radical, d) separation of the products in the form of a mixture R, S into R and S. Variant of the process according to claim 9, characterized in that the O-substituted hydroxylamine of formula (V) is condensed to the product of formula (XII):

to lead to the product of formula (XI) as defined in claim 9. As medicaments, the products corresponding to formula (I) as defined in claim 1, in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and A are as defined in claim 1 and R ₇ represents a hydrogen atom or an alkyloxycarbonyl radical, in which the alkyloxy radical contains from 1 to 4 carbon atoms, with the exception of tert-butyloxy, as well as their pharmaceutically acceptable acid salts. As medicaments, the products as defined in any one of claims 2 to 8, as well as their pharmaceutically acceptable acid salts. Pharmaceutical compositions containing, as active principle, at least one medicament according to one of claims 11 or 12. As new industrial products, the products of formulas (IV), (V), (VII), (IX), (X) and (XI) as defined in claim 9.